Bis-quinazoline compounds for the treatment of bacterial infections

Abstract

Bis-quinazoline compounds based on the compound (3,4-Dihydro-quinazolin-2-yl)-quinazolin-2-yl-amine, and methods of use of the compounds as inhibitors of bacterial DNA polymerase holoenzymes and in the treatment of bacterial infections are described.

1 . A compound of formula (I):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 2 , R 4 , and R 4 ′ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, CH 2 -aryl, CH 2 -heterocyclic, and phenyl; and  
 wherein  
 R 5 , R 5 ′, R 6 , R 6 ′, R 7 , R 7 ′, R 8 , and R 8 ′ are independently selected from the group consisting of hydrogen, halo, nitro, cyano, and hydroxy, C (1-7) alkyl (optionally substituted by halo, hydroxy, amino), mono to perfluoro C (1-3) alkyl, C (3-7) cycloalkyl, C (1-7) alkoxy, amino, mono- or di-C (1-6) alkylamino, C (1-7) alkylthio, benzyloxy, alkenyl, O-alkenyl, S-alkenyl, NH-alkenyl, alkynyl, O-alkynyl, S-alkynyl, NH-alkynyl, CH 2 -aryl, CH 2 -heterocyclic, aryl, heterocyclic, S-aryl, O-aryl, NH-aryl, phenyl, O-carbohydrate, S-carbohydrate, NH-carbohydrate, sulfamoyl, carbamoyl, N-alkyl fused to aryl or heterocyclic, OCOR 9 , SCOR 9 , NHCOR 9 , NHR 9 R 10 ; wherein R 9  and R 10  are independently selected from the group consisting of alkyl, aryl, including heterocyclic, and acyl donors selected from the group consisting of alkyl acids, amino acids, and aromatic acids;  
 and a cyclic ring connecting any of R 5  and R 6 ; R 6  and R 7 ; R 7  and R 8 ; R 5 ′ and R 6 ′; R 6 ′ and R 7 ′; and R 7 ′ and R 8 ′, wherein the cyclic ring is selected from the group consisting of methylenedioxy, dioxane, substituted methylenedioxy, heteroatom five member ring, and heteroatom six member ring; and  
 wherein  
 R 6 , R 7 , and R 6 ′ may also be further independently selected from the group consisting of Linker-Q,  
 wherein  
 Linker is a C 1-10  straight chain or branched alkyl, alkenyl, or alkynyl; wherein one or more methylene groups are optionally independently replaced by O, N or S; and wherein said linker is optionally substituted with 0-2 oxo groups and one or more C 1-4  branched or unbranched alkyl which may be substituted by one or more halogen atoms; and  
 wherein  
 Q is selected from the group consisting of phenyl; naphthyl; pyridine; pyrimidine; pyridazine; imidazole; benzimidazole; pyrazole; triazole; furan; thiophene; pyran; naphthyridine; oxazo[4,5-b]pyridine; and imidazo[4,5-b]pyridine; each of which may be optionally substituted with one to three groups selected from the group of halogen, C 1-6  alkyl, C 1-6  alkoxy, hydroxy, mono- or di-(C 1-3  alkyl)amino, C 1-6  alkyl-S(O) m  and phenylamino, wherein the phenyl ring is optionally substituted with one to two groups from the group halogen, C 1-6  alkyl and C 1-6  alkoxy;  
 tetrahydropyran; tetrahydrofuran; 1,3-dioxolanone; 1,3-dioxanone; 1,4-dioxane; morpholine; thiomorpholine; thiomorpholine sulfoxide; thiomorpholine sulfone; piperidine; piperazine; piperidinone; pyrrolidine; tetrahydrpyrimidone; cyclohexanone; cyclohexanol; each of which may be optionally substituted with one to three groups selected from the group consisting of C 1-6  alkyl, C 1-6  alkoxy, hydroxy, mono- or di-(C 1-3  alkyl)amino-C 1-3  alkyl, phenylamino-C 1-3  alkyl and C 1-3  alkoxy-C 1-3  alkyl;  
 C 1-6  alkoxy; secondary or tertiary amine wherein the amino nitrogen is covalently bonded to groups selected from the group consisting of C 1-6  alkyl, C 1-5  alkoxyalkyl, C 1-6  branched alkyl, each of which are optionally substituted with halo, hydroxy, or amino;  
 secondary or tertiary amine wherein the amino nitrogen is covalently bonded to phenyl, C 1-2  alkylphenyl or C 1-2  alkylpyridyl, wherein the aryl ring is optionally substituted with one to two groups selected from the group consisting of halogen, C 1-6  alkoxy, and hydroxy.  
 
     
     
         2 . A compound of  claim 1 , wherein linker is selected from the group consisting of ethoxy, methoxy, or propoxy.  
     
     
         3 . A compound of  claim 1 , wherein said compound is selected from the group consisting of 6-Methoxy-4-methyl-quinazolin-2-yl)-(4-methoxy-quinazolin-2-yl)-methyl-amine; 
 2-[(6-Methoxy-4-methyl-quinazolin-2-yl)-methyl-amino]-quinazolin-4-ol;    2-(4-Fluoromethyl-6-methoxy-quinazolin-2-ylamino)-quinazolin-4-ol;    2-(4-Ethyl-6-methoxy-quinazolin-2-ylamino)-quinazolin-4-ol;    2-(6-Methoxy-4-propyl-quinazolin-2-ylamino)-quinazolin-4-ol;    2-(4-Fluoromethyl-6,7-dimethoxy-quinazolin-2-ylamino)-8-methoxy-quinazolin-4-ol; and    2-(4-Fluoromethyl-6,7-dimethoxy-quinazolin-2-ylamino)-5-methoxy-quinazolin-4-ol.    
     
     
         4 . The compound of  claim 1 , wherein said compound is a compound of formula (II):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 5 , R 5 ′, R 6 , R 6 ′, R 7 , R 7 ′, R 8 , and R 8 ′ are independently selected from the group consisting of hydrogen; halo; hydroxy; C (1-7) alkyl (optionally substituted by halo, hydroxy, amino); mono to perfluoro C (1-3) alkyl; C (3-7) cycloalkyl; C (1-7) alkoxy; amino; and mono- or di-C (1-6) alkylamino; and a cyclic ring connecting any of R 5  and R 6 ; R 6  and R 7 ; R 7  and R 8 ; R 5 ′ and R 6 ′; R 6 ′ and R 7 ′; and R 7 ′ and R 8 ′, wherein the cyclic ring is selected from the group consisting of methylenedioxy, dioxane, substituted methylenedioxy, heteroatom five member ring, and heteroatom six member ring; and  
 wherein  
 R 6 , R 7 , and R 6 ′ may also be further independently selected from the group consisting of Linker-Q,  
 wherein  
 Linker is a C 1-6  straight chain or branched alkyl, alkenyl, or alkynyl, wherein one or more methylene groups are optionally independently replaced by O, N or S; and wherein said Linker is optionally substituted with 0-2 oxo groups and one or more C 1-4  branched or unbranched alkyl which may be substituted by one or more halogen atoms; and  
 Q is selected from the group consisting of pyridine, pyrazole, triazole, morpholine, piperidine, piperazine, pyrrolidine, each of which may be optionally substituted;  
 C 1-4  alkoxy; secondary or tertiary amine wherein the amino nitrogen is covalently bonded to groups selected from the group consisting of C 1-4  alkyl, C 1-5  alkoxyalkyl, and C 1-6  branched alkyl, each of which may be optionally substituted with halo, hydroxy, or amino;  
 secondary or tertiary amine wherein the amino nitrogen is covalently bonded to groups selected from phenyl, C 1-2  alkylphenyl and C 1-2  alkylpyridyl, wherein the aryl ring is optionally substituted with one to two groups selected from the group consisting of halogen, C 1-3  alkoxy, and hydroxy:  
 
     
     
         5 . A compound of  claim 4 , wherein said compound is selected from the group consisting of 2-(4-Hydroxy-quinazolin-2-ylamino)-4-methyl-quinazolin-6-ol; 
 6,7,8-Trimethoxy-2-(6-methoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol trifluoroacetate salt;    2-(6-Methoxy-4-methyl-quinazolin-2-ylamino)-6,8-dimethyl-quinazolin-4-ol;    2-(6-Methoxy-quinazolin-2-ylamino)-8-methyl-quinazolin-4-ol;    2-(6-Methoxy-4-methyl-quinazolin-2-ylamino)-8-methyl-6-nitro-quinazolin-4-ol;    6-Amino-2-(6-methoxy-4-methyl-quinazolin-2-ylamino)-8-methyl-quinazolin-4-ol trifluoroacetate salt;    6-N-methylamino-2-(6-methoxy-4-methyl-quinazolin-2-ylamino)-8-methyl-quinazolin-4-ol trifluoroacetate salt;    6-N-dimethylamino-2-(6-methoxy-4-methyl-quinazolin-2-ylamino)-8-methyl-quinazolin-4-ol trifluoroacetate salt;    7-Fluoro-2-(6-methoxy-4-methyl-quinazolin-2-ylamino)-6-nitro-quinazolin-4-ol trifluoroacetate salt;    2-(8-Methoxy-4-methyl-5-nitro-quinazolin-2-ylamino)-quinazolin-4-ol trifluoroacetate salt;    2-(5,8-Dimethoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol trifluoroacetate salt;    2-(5,6,7-Trimethoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol trifluoroacetate salt;    2-(5-Methoxy-4,8-dimethyl-quinazolin-2-ylamino)-quinazolin-4-ol trifluoroacetate salt;    2-(8-Methoxy-4-methyl-5-nitro-quinazolin-2-ylamino)-6,8-dimethyl-quinazolin-4-ol, trifluoroacetate salt;    4-Hydroxy-2-(6-methoxy-4-methyl-quinazolin-2-ylamino)-quinazoline-7-carboxylic acid;    2-(7-Fluoro-6-methoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol trifluoroacetate salt;    6-Chloro-2-(6-methoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol;    2-(4-Methyl-6-methylsulfanyl-quinazolin-2-ylamino)-quinazolin-4-ol trifluoroacetate salt;    6,8-Dimethyl-2-(5,6,7-trimethoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol trifluoroacetate salt;    5-Methoxy-2-(6-methoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol trifluoroacetate salt;    N-[4-Hydroxy-2-(6-methoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-6-yl]-acetamide trifluoroacetate salt;    8-Bromo-2-(6-methoxy-4-methyl-quinazolin-2-ylamino)-6-methyl-quinazolin-4-ol trifluoroacetate salt;    2-(5-Methoxy-4,8-dimethyl-quinazolin-2-ylamino)-6,8-dimethyl-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6,8-dimethyl-quinazolin-4-ol trifluoroacetate salt;    2-(2,2-Difluoro-8-methyl-[1,3]dioxolo[4,5-g]quinazolin-6-ylamino)-quinazolin-4-ol trifluoroacetate salt;    2-(5,8-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6,8-dimethyl-quinazolin-4-ol trifluoroacetate salt;    2-(7-Fluoro-6-methoxy-4-methyl-quinazolin-2-ylamino)-6,8-dimethyl-quinazolin-4-ol trifluoroacetate salt;    2-(6,8-Dimethoxy-4-methyl-quinazolin-2-ylamino)-8-methyl-quinazolin-4-ol trifluoroacetate salt;    6-Amino-2-(6-methoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol; trifluoroacetate salt;    2-(8-Methoxy-4-methyl-quinazolin-2-ylamino)-6,8-dimethyl-quinazolin-4-ol;    2-(8-Methoxy-4-methyl-quinazolin-2-ylamino)-8-methyl-quinazolin-4-ol;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol;    2-(6-Methoxy-4-methyl-quinazolin-2-ylamino)-6-nitro-quinazolin-4-ol;    2-(6-Methoxy-4-methyl-quinazolin-2-ylamino)-7-nitro-quinazolin-4-ol;    5-Fluoro-2-(6-methoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol;    6-Fluoro-2-(6-methoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol;    7-Fluoro-2-(6-methoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol;    2-(8-Methoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol;    2-(8-Ethoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol;    2-(6-Methoxy-4-methyl-quinazolin-2-ylamino)-quinazoline-4,6-diol;    6-Methoxy-2-(6-methoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol;    6,7-Dimethoxy-2-(6-methoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol;    2-(6-Methoxy-4-methyl-quinazolin-2-ylamino)-6-methyl-quinazolin-4-ol;    2-(6-Methoxy-4-methyl-quinazolin-2-ylamino)-7-methyl-quinazolin-4-ol;    2-(6-Methoxy-4-methyl-quinazolin-2-ylamino)-8-methyl-quinazolin-4-ol;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-8-methyl-6-nitro-quinazolin-4-ol trifluoroacetate salt;    2-(6,8-Dimethoxy-4-methyl-quinazolin-2-ylamino)-8-methyl-6-nitro-quinazolin-4-ol trifluoroacetate salt;    2-(8-Methoxy-4-methyl-quinazolin-2-ylamino)-8-methyl-6-nitro-quinazolin-4-ol trifluoroacetate salt;    2-[6-(2-Methoxy-ethoxy)-4-methyl-quinazolin-2-ylamino]-8-methyl-6-nitro-quinazolin-4-ol trifluoroacetate salt;    6-Amino-2-[6-(2-methoxy-ethoxy)-4-methyl-quinazolin-2-ylamino]-8-methyl-quinazolin-4-ol trifluoroacetate salt;    2-(6-Methoxy-4-methyl-quinazolin-2-ylamino)-quinazoline-4,8-diol trifluoroacetate salt;    2-(8-Methoxy-4-methyl-quinazolin-2-ylamino)-quinazoline-4,8-diol trifluoroacetate salt;    2-(7,8-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6,8-dimethyl-quinazolin-4-ol trifluoroacetate salt;    2-(7,8-Dimethoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol trifluoroacetate salt;    2-(6,8-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6,8-dimethyl-quinazolin-4-ol trifluoroacetate salt;    2-(6-methoxy-7-amino-4-methyl-quinazolin-2-ylamino)-8-methoxy-quinazolin-4-ol trifluoroacetate salt;    2-(6-methoxy-7-nitro-4-methyl-quinazolin-2-ylamino)-8-methoxy-quinazolin-4-ol trifluoroacetate salt;    2-(7,8-Dimethoxy-4-methyl-quinazolin-2-ylamino)-8-methoxy-quinazolin-4-ol trifluoroacetate salt;    8-Methoxy-2-[6-methoxy-8-(2-methoxy-ethoxy)-4-methyl-quinazolin-2-ylamino]-quinazolin-4-ol trifluoroacetate salt;    8-Methoxy-2-[6-(2-methoxy-ethoxy)-4-methyl-quinazolin-2-ylamino]-quinazolin-4-ol trifluoroacetate salt;    8-Methoxy-2-[7-methoxy-8-(2-methoxy-ethoxy)-4-methyl-quinazolin-2-ylamino]-quinazolin-4-ol trifluoroacetate salt;    8-Methoxy-2-(8-methyl-2,3-dihydro-1,4-dioxa-5,7-diaza-phenanthren-6-ylamino)-quinazolin-4-ol;    5-ethoxy-2-(8-methyl-2,3-dihydro-1,4-dioxa-5,7-diaza-phenanthren-6-ylamino)-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-5-methoxy-quinazolin-4-ol trifluoroacetate salt;    2-(6,8-Dimethoxy-4-methyl-quinazolin-2-ylamino)-5-methoxy-quinazolin-4-ol trifluoroacetate salt;    2-(7-Fluoro-6-methoxy-4-methyl-quinazolin-2-ylamino)-8-methoxy-quinazolin-4-ol trifluoroacetate salt;    5-Methoxy-2-[6-(2-methoxy-ethoxy)-4-methyl-quinazolin-2-ylamino]-quinazolin-4-ol trifluoroacetate salt;    2-[6,7-Bis-(2-methoxy-ethoxy)-4-methyl-quinazolin-2-ylamino]-8-methoxy-quinazolin-4-ol trifluoroacetate salt;    8-Methoxy-2-(5-methoxy-4,8-dimethyl-quinazolin-2-ylamino)-quinazolin-4-ol trifluoroacetate salt;    8-Methyl-2-(5-methoxy-4,8-dimethyl-quinazolin-2-ylamino)-quinazolin-4-ol trifluoroacetate salt;    2-(6,8-Dimethoxy-4-methyl-quinazolin-2-ylamino)-quinazoline-4,5-diol trifluoroacetate salt;    2-(7-Fluoro-6-methoxy-4-methyl-quinazolin-2-ylamino)-5-methoxy-quinazolin-4-ol trifluoroacetate salt;    5,8-Dimethoxy-2-(8-methyl-2,3-dihydro-1,4-dioxa-5,7-diaza-phenanthren-6-ylamino)-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-8-fluoro-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-8-ethoxy-quinazolin-4-ol trifluoroacetate salt;    2-(6,8-Dimethoxy-4-methyl-quinazolin-2-ylamino)-8-fluoro-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-5,8-dimethoxy-quinazolin-4-ol trifluoroacetate salt;    2-(6,8-Dimethoxy-4-methyl-quinazolin-2-ylamino)-5,8-dimethoxy-quinazolin-4-ol trifluoroacetate salt;    [2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-4-hydroxy-quinazolin-6-yloxy]-acetonitrile;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-(2-methoxy-ethoxy)-quinazolin-4-ol trifluoroacetate salt;    2-(4-Hydroxy-8-methoxy-quinazolin-2-ylamino)-6-methoxy-4-methyl-quinazolin-7-ol trifluoroacetate salt;    2-(8-Fluoro-4-hydroxy-quinazolin-2-ylamino)-6-methoxy-4-methyl-quinazolin-7-ol trifluoroacetate salt;    6-(2-Chloro-ethoxy)-2-(6,7-dimethoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol trifluoroacetate salt;    6-(3-Chloro-propoxy)-2-(6,7-dimethoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol trifluoroacetate salt;    6-(2-Chloro-ethoxy)-2-(6,8-dimethoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol trifluoroacetate salt;    8-Fluoro-2-(4-methyl-7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-2-ylamino)-quinazolin-4-ol trifluoroacetate salt;    7-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-1,3-dioxa-6,8-diaza-cyclopenta[a]naphthalen-9-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-5-isopropoxy-quinazolin-4-ol trifluoroacetate salt;    2-(6,8-Dimethoxy-4-methyl-quinazolin-2-ylamino)-5-isopropoxy-quinazolin-4-ol trifluoroacetate salt;    2-(6,8-Dimethoxy-4-methyl-quinazolin-2-ylamino)-5-ethoxy-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-piperidin-1-yl-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-morpholin-4-yl-quinazolin-4-ol trifluoroacetate salt;    2-[6-(2-Diethylamino-ethoxy)-4-methyl-quinazolin-2-ylamino]-8-methoxy-quinazolin-4-ol trifluoroacetate salt;    8-Methoxy-2-(6,7,8-trimethoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol trifluoroacetate salt;    2-(7-Fluoro-8-methoxy-4-methyl-quinazolin-2-ylamino)-8-methoxy-quinazolin-4-ol trifluoroacetate salt;    8-Fluoro-2-(6,7,8-trimethoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol trifluoroacetate salt;    8-Fluoro-2-(7-fluoro-8-methoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol trifluoroacetate salt;    6-Amino-2-(6,7-dimethoxy-4-methyl-quinazolin-2-ylamino)-8-methyl-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-dimethylamino-8-methyl-quinazolin-4-ol trifluoroacetate salt;    8-Amino-2-(6-methoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol trifluoroacetate salt;    6-Amino-2-(6-methoxy-4-methyl-quinazolin-2-ylamino)-8-methoxy-quinazolin-4-ol trifluoroacetate salt;    6-Amino-2-(6,8-dimethoxy-4-methyl-quinazolin-2-ylamino)-8-methoxy-quinazolin-4-ol trifluoroacetate salt;    6-Amino-2-[6-(2-diethylamino-ethoxy)-4-methyl-quinazolin-2-ylamino]-8-methyl-quinazolin-4-ol trifluoroacetate salt;    6-Amino-2-(6,8-dimethoxy-4-methyl-quinazolin-2-ylamino)-8-methyl-quinazolin-4-ol trifluoroacetate salt;    2-(7-Dimethylamino-6-methoxy-4-methyl-quinazolin-2-ylamino)-8-methoxy-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-5-dimethylamino-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-(2H-tetrazol-5-ylmethoxy)-quinazolin-4-ol trifluoroacetate salt;    7-(6,8-Dimethoxy-4-methyl-quinazolin-2-ylamino)-1,3-dioxa-6,8-diaza-cyclopenta[a]naphthalen-9-ol trifluoroacetate salt;    7-(6,8-Dimethoxy-4-methyl-quinazolin-2-ylamino)-1,3-dioxa-6,8-diaza-cyclopenta[a]naphthalen-9-ol HCl salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-5,6-dimethoxy-quinazolin-4-ol TFA salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-5,6-dimethoxy-quinazolin-4-ol HCl salt;    2-(6,8-Dimethoxy-4-methyl-quinazolin-2-ylamino)-5,6-dimethoxy-quinazolin-4-ol TFA salt;    2-(6,8-Dimethoxy-4-methyl-quinazolin-2-ylamino)-5,6-dimethoxy-quinazolin-4-ol HCl salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-(2-hydroxy-ethoxy)-quinazolin-4-ol trifluoroacetate salt;    2-(6,8-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-(2-hydroxy-ethoxy)-quinazolin-4-ol trifluoroacetate salt;    6-[2-(3-Hydroxy-pyrrolidin-1-yl)-ethoxy]-2-(8-methoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-{2-[(2-hydroxy-ethyl)-methyl-amino]-ethoxy}-quinazolin-4-ol trifluoroacetate salt;    2-(6,8-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-{2-[(2-hydroxy-ethyl)-methyl-amino]-ethoxy}-quinazolin-4-ol trifluoroacetate salt;    2-(6,8-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-(2-morpholin-4-yl-ethoxy)-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-[2-(1-hydroxymethyl-2-methyl-propylamino)-ethoxy]-quinazolin-4-ol Trifluoroacetate salt;    2-(6,8-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-[2-(2-hydroxy-1-methyl-ethylamino)-ethoxy]-quinazolin-4-ol trifluoroacetate salt;    6-(2-Diethylamino-ethoxy)-2-(6,8-dimethoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-(2-piperidin-1-yl-ethoxy)-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-(2-dimethylamino-ethoxy)-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-[2-(4-methyl-piperazin-1-yl)-ethoxy]-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-(2-pyrrolidin-1-yl-ethoxy)-quinazolin-4-ol trifluoroacetate salt;    6-(2-Diethylamino-ethoxy)-2-(6,7-dimethoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol trifluoroacetate salt;    2-[4-Hydroxy-6-(2-morpholin-4-yl-ethoxy)-quinazolin-2-ylamino]-6,7-dimethoxy-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-(3-pyrrolidin-1-yl-propoxy)-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-(2-pyrrol-1-yl-ethoxy)-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-(2-pyrrolidin-1-yl-ethoxy)-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-[2-(3-hydroxy-pyrrolidin-1-yl)-ethoxy]-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-[2-(3-hydroxy-pyrrolidin-1-yl)-ethoxy]-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-[2-(3-hydroxy-pyrrolidin-1-yl)-ethoxy]-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-[2-(3-hydroxy-piperidin-1-yl)-ethoxy]-quinazolin-4-ol trifluoroacetate salt;    6-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethoxy}-2-(6,7-dimethoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-{2-[ethyl-(2-hydroxy-ethyl)-amino]-ethoxy}-quinazolin-4-ol trifluoroacetate salt;    2-(6,8-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-[2-(3-hydroxy-pyrrolidin-1-yl)-ethoxy]-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-[2-(2-hydroxy-ethylamino)-ethoxy]-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-{2-[(1-hydroxymethyl-3-methyl butyl)-amino]-ethoxy}-quinazolin-4-ol Trifluoroacetate salt;    6-[2-(3-Amino-pyrrolidin-1-yl)-ethoxy]-2-(6,7-dimethoxy-4-methyl-quinazolin-2-ylamino)-quinazolin-4-ol;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-[2-(2-hydroxymethyl-pyrrolidin-1-yl)-ethoxy]-quinazolin-4-ol trifluoroacetate salt;    2-{2-[2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-4-hydroxy-quinazolin-6-yloxy]-ethylamino}-propane-1,3-diol trifluoroacetate salt;    2-(6,8-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-(2-pyrrolidin-1-yl-ethoxy)-quinazolin-4-ol trifluoroacetate salt;    2-(6,8-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-{2-[ethyl-(2-hydroxy-ethyl)-amino]-ethoxy}-quinazolin-4-ol trifluoroacetate salt;    2-(6,8-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-[2-(2-hydroxymethyl-pyrrolidin-1-yl)-ethoxy]-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-[2-(2-hydroxy-1-methyl-ethylamino)-ethoxy]-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-[2-(2-hydroxymethyl-morpholin-4-yl)-ethoxy]-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-{2-[(2-dimethylamino-ethyl)-ethyl-amino]-ethoxy}-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-[2-(morpholin-4-ylamino)-ethoxy]-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-[2-(2-hydroxymethyl-piperidin-1-yl)-ethoxy]-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-(2-[1,2,4]triazol-4-yl-ethoxy)-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-{2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-ethoxy}-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-{2-[N′-(2-hydroxy-ethyl)-hydrazino]-ethoxy}-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-[2-(2,6-dimethyl-morpholin-4-yl)-ethoxy]-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-{N′,N′-dimethyl-hydrazino]-ethoxy}-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-{2-[2-(2-hydroxy-ethoxy)-ethylamino]-ethoxy}-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-[2-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-ethoxy]-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-[2-(2-hydroxy-cyclohexylamino)-ethoxy]-quinazolin-4-ol trifluoroacetate salt;    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-[2-(methyl-pyridin-3-ylmethyl-amino)-ethoxy]-quinazolin-4-ol trifluoroacetate salt    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-[2-(2-pyridin-4-yl-ethylamino)-ethoxy]-quinazolin-4-ol TFA salt; and    2-(6,7-Dimethoxy-4-methyl-quinazolin-2-ylamino)-6-[2-(methyl-pyridin-4-ylmethyl-amino)-ethoxy]-quinazolin-4-ol TFA salt;    
     
     
         5 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt of a compound of  claim 1 .  
     
     
         6 . A pharmaceutical composition comprising a compound of  claim 4  or a pharmaceutically acceptable salt of a compound of  claim 4 .  
     
     
         7 . A method of treatment, comprising: 
 a) providing a patient having a bacterial infection; and    b) administering the of compound of  claim 1  or a pharmaceutically acceptable salt of a compound of  claim 1  to said patient.    
     
     
         8 . A method of treatment, comprising: 
 a) providing a patient having a bacterial infection; and    b) administering compound of compound of  claim 4  or a pharmaceutically acceptable salt of a compound of  claim 4  to said patient.    
     
     
         9 . A method of preparing a bis-quinazoline compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 4 , and R 4 ′ are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, CH 2 -aryl, CH 2 -heterocyclic, and phenyl; and  
 wherein  
 R 5 , R 5 ′, R 6 , R 6 ′, R 7 , R 7 ′, R 8 , and R 8 ′ are independently selected from the group consisting of hydrogen, halo, nitro, cyano, and hydroxy, C (1-7) alkyl (optionally substituted by halo, hydroxy, amino), mono to perfluoro C (1-3) alkyl, C (3-7) cycloalkyl, C (1-7) alkoxy, amino, mono- or di-C (1-6) alkylamino, C (1-7) alkylthio, benzyloxy, alkenyl, O-alkenyl, S-alkenyl, NH-alkenyl, alkynyl, O-alkynyl, S-alkynyl, NH-alkynyl, CH 2 -aryl, CH 2 -heterocyclic, aryl, heterocyclic, S-aryl, O-aryl, NH-aryl, phenyl, O-carbohydrate, S-carbohydrate, NH-carbohydrate, sulfamoyl, carbamoyl, N-alkyl fused to aryl or heterocyclic, OCOR 9 , SCOR 9 , NHCOR 9 , NHR 9 R 10 ; whereinR 9  and R 10  are independently selected from the group consisting of alkyl, aryl, including heterocyclic, and acyl donors selected from the group consisting of alkyl acids, amino acids, and aromatic acids;  
 and a cyclic ring connecting any of R 5  and R 6 ; R 6  and R 7 ; R 7  and R 8 ; R 5 ′ and R 6 ′; R 6 ′ and R 7 ′; and R 7 ′ and R 8 ′, wherein the cyclic ring is selected from the group consisting of methylenedioxy, dioxane, substituted methylenedioxy, heteroatom five member ring, and heteroatom six member ring;  
 comprising:  
 a) providing a salt of an aniline of the formula  
                     
 b) reacting it with sodium dicyanamide to generate a quinazolin-2-yl-cyanamide of the formula:  
                     
 and  
 c) reacting the quinazolin-2-yl-cyanamide with an alkyl anthranilate of the formula:  
                     
 in the presence of a concentrated acid to generate a bis-quinazoline compound of the formula:  
                     
 
     
     
         10 . The method of  claim 9 , wherein the concentrated acid is selected from the group consisting of hydrochloric acid, sulfuric acid, and phosphoric acid.  
     
     
         11 . A method of preparing a bis-quinazoline compound of the formula:  
       
         
           
           
               
               
           
         
         R 4  is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, CH 2 -aryl, CH 2 -heterocyclic, and phenyl; and  
         wherein  
         R 5 , R 5 ′, R 6 , R 6 ′, R 7 , R 7 ′, R 8 , and R 8 ′ are independently selected from the group consisting of hydrogen, halo, nitro, cyano, and hydroxy, C (1-7) alkyl (optionally substituted by halo, hydroxy, amino), mono to perfluoro C (1-3) alkyl, C (3-7) cycloalkyl, C (1-7) alkoxy, amino, mono- or di-C (1-6) alkylamino, C (1-7) alkylthio, benzyloxy, alkenyl, O-alkenyl, S-alkenyl, NH-alkenyl, alkynyl, O-alkynyl, S-alkynyl, NH-alkynyl, CH 2 -aryl, CH 2 -heterocyclic, aryl, heterocyclic, S-aryl, O-aryl, NH-aryl, phenyl, O-carbohydrate, S-carbohydrate, NH-carbohydrate, sulfamoyl, carbamoyl, N-alkyl fused to aryl or heterocyclic, OCOR 9 , SCOR 9 , NHCOR 9 , NHR 9 R 10 ; whereinR 9  and R 10  are independently selected from the group consisting of alkyl, aryl, including heterocyclic, and acyl donors selected from the group consisting of alkyl acids, amino acids, and aromatic acids;  
         and a cyclic ring connecting any of R 5  and R 6 ; R 6  and R 7 ; R 7  and R 8 ; R 5 ′ and R 6 ′; R 6 ′ and R 7 ′; and R 7 ′ and R 8 ′, wherein the cyclic ring is selected from the group consisting of methylenedioxy, dioxane, substituted methylenedioxy, heteroatom five member ring, and heteroatom six member ring;  
         comprising:  
         a) providing a quinazolin-2-yl guanidine of the formula:  
         
           
             
             
                 
                 
             
           
         
         and  
         b) reacting said quinazolin-2-yl guanidine with an isatoic anhydride of the formula:  
         
           
             
             
                 
                 
             
           
         
         in the presence of a tertiary amine to generate a bis-quinazoline compound of the formula:  
         
           
             
             
                 
                 
             
           
         
       
     
     
         12 . The method of  claim 11 , wherein the tertiary amine is selected from the group consisting of diiopropyethylamine and triethylamine.  
     
     
         13 . A method of preparing a bis-quinazoline compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 n is an integer from 1-10; and  
 wherein  
 R 5 , R 6 , R 7 , and R 8  are independently selected from the group consisting of hydrogen, halo, nitro, cyano, and hydroxy, C (1-7) alkyl (optionally substituted by halo, hydroxy, amino), mono to perfluoro C (1-3) alkyl, C (3-7) cycloalkyl, C (1-7) alkoxy, amino, mono- or di-C (1-6) alkylamino, C (1-7) alkylthio, benzyloxy, alkenyl, O-alkenyl, S-alkenyl, NH-alkenyl, alkynyl, O-alkynyl, S-alkynyl, NH-alkynyl, CH 2 -aryl, CH 2 -heterocyclic, aryl, heterocyclic, S-aryl, O-aryl, NH-aryl, phenyl, O-carbohydrate, S-carbohydrate, NH-carbohydrate, sulfamoyl, carbamoyl, N-alkyl fused to aryl or heterocyclic, OCOR 9 , SCOR 9 , NHCOR 9 , NHR 9 R 10 ; whereinR 9  and R 10  are independently selected from the group consisting of alkyl, aryl, including heterocyclic, and acyl donors selected from the group consisting of alkyl acids, amino acids, and aromatic acids;  
 and a cyclic ring connecting any of R 5  and R 6 ; R 6  and R 7 ; R 7  and R 8 ; wherein the cyclic ring is selected from the group consisting of methylenedioxy, dioxane, substituted methylenedioxy, heteroatom five member ring, and heteroatom six member ring; and  
 wherein  
 Q is selected from the group consisting of phenyl; naphthyl; pyridine; pyrimidine; pyridazine; imidazole; benzimidazole; pyrazole; triazole; furan; thiophene; pyran; naphthyridine; oxazo[4,5-b]pyridine; and imidazo[4,5-b]pyridine; each of which may be optionally substituted with one to three groups selected from the group of halogen, C 1-6  alkyl, C 1-6  alkoxy, hydroxy, mono- or di-(C 1-3  alkyl)amino, C 1-6  alkyl-S(O) m  and phenylamino, wherein the phenyl ring is optionally substituted with one to two groups from the group halogen, C 1-6  alkyl and C 1-6  alkoxy;  
 tetrahydropyran; tetrahydrofuran; 1,3-dioxolanone; 1,3-dioxanone; 1,4-dioxane; morpholine; thiomorpholine; thiomorpholine sulfoxide; thiomorpholine sulfone; piperidine; piperazine; piperidinone; pyrrolidine; tetrahydrpyrimidone; cyclohexanone; cyclohexanol; each of which may be optionally substituted with one to three groups selected from the group consisting of C 1-6  alkyl, C 1-6  alkoxy, hydroxy, mono- or di-(C 1-3  alkyl)amino-C 1-3  alkyl, phenylamino-C 1-3  alkyl and C 1-3  alkoxy-C 1-3  alkyl;  
 C 1-6  alkoxy; secondary or tertiary amine wherein the amino nitrogen is covalently bonded to groups selected from the group consisting of C 1-6  alkyl, C 1-5  alkoxyalkyl, C 1-6  branched alkyl, each of which are optionally substituted with halo, hydroxy, or amino;  
 secondary or tertiary amine wherein the amino nitrogen is covalently bonded to phenyl, C 1-2  alkylphenyl or C 1-2  alkylpyridyl, wherein the aryl ring is optionally substituted with one to two groups selected from the group consisting of halogen, C 1-6  alkoxy, and hydroxyl; comprising:  
 a) providing a bis-quinazolin-2-yl-amine of the formula:  
                     
 wherein X is selected from the group consisting of Cl, Br, and I;  
 b) reacting said bis-quinazolin-2-yl-amine with a nucleophile, and  
 c) heating the resulting mixture to generate a bis-quinazoline compound of the formula:  
                     
 
     
     
         14 . The method of  claim 13 , wherein said nucleophile is selected from the group consisting of a primary amine, a secondary amine, a primary alcohol, a secondary alcohol, a primary alkoxide, a secondary alkoxide, and alkali metal, and an alkali metal hydroxide.